RESUMO
Retinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies. However, limitations associated with anti-VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled-7 (Fzd7) pathway in a mouse model of oxygen-induced retinopathy (OIR). Using transgenic mice, which enabled endothelium-specific and time-specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso-obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAbFzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/ß-catenin and Jagged1 expression to control EC proliferation in extra-retinal neovessels. We identified Fzd7/ß-catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies.
Assuntos
Retinopatia Diabética/metabolismo , Isquemia/metabolismo , Proteínas Repressoras/metabolismo , Neovascularização Retiniana/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Deleção de Genes , Isquemia/genética , Isquemia/patologia , Proteína Jagged-1/biossíntese , Proteína Jagged-1/genética , Camundongos , Camundongos Mutantes , Proteínas Repressoras/genética , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia , beta Catenina/genéticaRESUMO
PURPOSE: To define the contribution of the corneal epithelium in corneal topography in keratoconus and discuss the implications regarding combined topography-guided photorefractive keratectomy and corneal collagen crosslinking (CXL). SETTING: French National Reference Center for Keratoconus, Bordeaux, France. DESIGN: Case series. METHODS: Specular topographies were performed before and immediately after epithelial removal during conventional CXL surgery in patients with keratoconus. RESULTS: The study included 1 eye with forme fruste keratoconus, 4 eyes in Krumeich stage I, and 3 eyes in stage II. The mean simulated maximum keratometry (K) increased by 2.87 diopters (D) after epithelial removal. The mean effective refractive power increased by a mean of 4.01 D and the astigmatic refractive power, by a mean of 2.17 D. The difference in mean axis deviation was not significant. The mean inferior-superior ratio irregularity index increased 1.51 units. All K and refractive readings except astigmatic refractive axis were significantly increased after epithelial removal. All regularity indices increased significantly without the epithelium. The amplitude of variations in K readings made it difficult to predict the refractive changes after custom laser photoablation based on epithelial-based topography. CONCLUSIONS: The astigmatism refractive axis did not change significantly; therefore, this axis could be useful for astigmatic corrections, whereas the spherical component would not be useful. Topographic changes after epithelial removal can be important but not intuitive in keratoconus eyes. This should be considered in custom topography-guided photoablation strategies when attempting to correct refractive errors at the time of CXL.
